Recent research has investigated the innovative possibilities of stem-cell based treatment for cardiovascular issues.

Specifically, extracellular vesicles derived from human vascular endothelial cells — which are cells that line blood vessels — are being discussed as possible candidates for therapeutic heart attack recovery treatment. The research analyzed the protein cargo of these vesicles, often derived from stem cells, for possible cardioprotective effects they may induce on damaged heart tissue following a heart attack.

A heart attack is induced by the blockage or restriction of blood flow that carries oxygen to the heart. When this occurs, the heart muscle that has lost blood flow becomes injured and forms scar tissue. 

However, scar tissue formed after a heart attack does not perform as well as healthy heart tissue. It can weaken the heart’s ability to pump and contract and promote the development of other cardiovascular complications in the future.   

In the United States, a heart attack occurs every 40 seconds, with over 800,000 Americans suffering a heart attack every year. The most common treatments for heart failure often necessitate a combination of lifestyle changes, medication, surgery and implanted devices to maintain heart rhythm. 

An advantage of stem cell therapy over these common maintenance-based treatments arises from its potential to target specific damage done to heart cells following a heart attack. Stem cells are cells that have the potential to develop or differentiate into any type of cell within the human body, and as a result, can be helpful in repairing tissue damage after a heart attack. 

One type of stem cell therapy that has been considered and tested in clinical trials involves using stem cells derived from bone marrow, which is the spongy tissue that is found inside bones of the human body. Stem cells taken from the bone marrow are directly injected into the heart and help regenerate damaged tissue. 

However, this type of stem cell therapy is still awaiting further research in order to investigate different mechanisms and cell sources that can lead to functional heart cells after injection.

Stem cell therapy can also utilize components within stem cells that can help facilitate the repair of a damaged organ without having to directly inject stem cells into the organ.

An example of such components are Extracellular Vesicles (EVs), particles secreted by either the endosome or plasma membrane of almost any type of cell, including stem cells. While originally, EVs were solely thought of as members of an excretion mechanism for cell waste, scientists now believe they also act as signaling vehicles and help exchange materials between cells. A particular EV of interest are exosomes derived from endothelial stem cells that provide signaling between cardiomyocytes, or cells that make up the heart muscle.

The study led by members of Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) expands on the particular cargo of exosomes that induce cardioprotective effects.

Previous to the study, the initially identified components carried by exosomes were microRNA (miRNA), small molecules that can regulate gene expression, acting as an “on-and-off” switch for different cellular processes.

For example, research has found that miRNA have the potential to curb cell death and prevent further cardiac damage induced by inflammation by suppressing apoptosis, or programmed cell death within the first ten days following a heart attack. The ability of miRNA to act relatively quickly makes their exosome carriers good candidates for treatments against potentially fatal cardiac events that are time sensitive.

However, in addition to miRNA, the Harvard and SEAS study was able to find over 1,800 proteins that have cardioprotective potential within the cargo of these exosomes.

The functionality of these proteins was able to be tested in-vitro, meaning outside of the living organism, using the “Heart-on-chip” device lined with human stem-cell derived heart tissue. This mechanism allows researchers to study the physiological environments of organs without having to expose the organs to these tests directly.

The protein cargo was tested by simulating an Ischemic-reperfusion injury (IRI), which is tissue damage resulting from the sudden return of blood supply to previously deoxygenated tissues, on the chip device.

In addition to tissue damage, a significant stressor induced by ischemia is a decrease in contractile capacity of the heart. Contractile capacity refers to the heart muscle’s innate ability and strength to contract during systole, which is when the blood in the heart is pumped to the aorta and pulmonary valve from its ventricles. A weakened contractile capacity can cause more dangerous complications, such as irregular heartbeats and an increased risk of heart failure.

Results from the simulation revealed that the presence of these proteins alleviated the loss in contractile capacity of the heart as well as the occurrence of cardiac cell death. Many of the proteins tested were found to have roles in cellular homeostasis and cell preservation, which ultimately aided in supporting cell longevity during the induced cardiac stress.

When compared to a control group of untreated tissues, tissues treated with the endothelial EVs that carry these proteins saw a 50% reduction in apoptosis and a recovery rate that was four times higher. 

Given the diversity of protein cargo of the tested extracellular vesicles and their resulting cardioprotective functions, the study concluded that EVs can be used as a multitarget therapy for heart attack recovery. This is an approach that would allow treatments implementing EVs to target and heal different factors of the heart’s physiology that have been damaged, such as its contractile capacity and tissue cell longevity, at the same time.

While these results introduce a potentially beneficial approach to heart attack therapy through the use of stem cell-derived EVs, the need to focus on technical factors when it comes to providing efficient stem-cell therapeutics will be of interest for future research. 

For example, current limitations, such as establishing the correct dosage and ensuring a safe and accessible transition to clinical applications, are yet to be more thoroughly discussed. 

For now, the established basis for stem cell-derived exosomal therapies provides a pathway for future work to uncover the application of stem cells in other treatments concerning heart health. 

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